Cytokine-mediated inhibition of astrocyte gap junction coupling as a cause of temporal lobe epilepsy

细胞因子介导的星形胶质细胞间隙连接耦合抑制是颞叶癫痫的原因

• 批准号: 511827070
• 负责人: Professor Dr. Christian Steinhäuser
• 金额: --
• 依托单位: Institut für Zelluläre Neurowissenschaften
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/511827070?language=en
• 关键词: Cytokine; mediated; inhibition; astrocyte; gap

Temporal lobe epilepsy (TLE) is the most common form of adult epilepsies. Current treatments only suppress seizures but do not cure the disorder, and are inefficient in more than 2/3 of the patients. Hence, new therapeutic strategies and targets are urgently needed. In this regard, astrocytes have attracted increasing attention during recent years, since it has become clear that they actively regulate neuronal excitability and synaptic transmission. We have previously shown that gap junction coupling between astrocytes, which plays a key role in buffering of enhanced extracellular K+ and glutamate levels during high neuronal activity, is rapidly impaired after initiation of experimental TLE, and completely absent in the chronic phase of the disease in both, patients and an animal model. Our recent data suggest that astrocyte uncoupling is mediated by the soluble form of the proinflammatory cytokine, TNFα. Remarkably, specific inhibition of soluble TNFα not only prevented seizure-induced uncoupling but also yielded significant antiepileptic and antiepileptogenic effects in our animal model. Thus, we hypothesize that release of microglial TNFα after an initial epileptogenic event triggers disruption of astrocytic gap junction coupling, which in turn plays a key role in the development and progression of TLE. To test this hypothesis, in the present application we will i) unravel the time course of cytokine expression and astrocyte uncoupling in experimental TLE, ii) test the microglial origin of TNFα and identify the molecular mechanism(s) of its influence on astrocyte functions, and iii) prove the crucial role of TNFα-induced astrocyte uncoupling as a cause of TLE. This project will increase our understanding of the mechanisms of epileptogenesis and elucidate the potential of targeting glial signaling pathways for developing new, disease-modifying therapeutic strategies.

颞叶癫痫(TLE)是成人癫痫最常见的表现形式。目前的治疗方法只抑制癫痫发作，而不能治愈这种疾病，而且对超过三分之二的患者无效。因此，迫切需要新的治疗策略和靶点。在这方面，星形胶质细胞近年来引起了越来越多的关注，因为很明显，它们积极地调节神经元的兴奋性和突触传递。我们之前已经证明，星形胶质细胞之间的缝隙连接偶联在高神经元活动期间对细胞外K+和谷氨酸水平的升高起着关键的缓冲作用，在实验性TLE开始后迅速受损，并在患者和动物模型的慢性期完全消失。我们最近的数据表明，星形胶质细胞的解偶联是由致炎细胞因子α的可溶性形式介导的。值得注意的是，在我们的动物模型中，特异性地抑制可溶性肿瘤坏死因子α不仅能阻止癫痫的解偶联，而且能产生显著的抗癫痫和抗癫痫作用。因此，我们推测，癫痫发作后小胶质细胞肿瘤坏死因子α的释放触发了星形胶质细胞缝隙连接偶联的破坏，这反过来在TLE的发生和发展中起着关键作用。为了验证这一假说，在本应用中，我们将1)揭示实验性TLE中细胞因子表达和星形胶质细胞解偶联的时间进程，2)检测肿瘤坏死因子α的小胶质细胞来源，并确定其影响星形胶质细胞功能的分子机制(S)，3)证明肿瘤坏死因子α诱导的星形胶质细胞解偶联是TLE的重要原因。这个项目将增加我们对癫痫发生机制的理解，并阐明靶向神经胶质信号通路的潜力，以开发新的、改变疾病的治疗策略。